Chemokine is known as a basic protein which has chemotaxis and an activating activity against endogenous leucocytes and also has strong heparin-binding abilities. It is now considered that chemokine is associated with not only control of infiltration of specific leucocytes upon inflammatory and immune responses, but also development, homing of lymphocytes under physiological conditions and migration of hemocyte precursor cells and somatic cells.
Differentiation, proliferation and cell death of blood cells are controlled by various cytokines. Inflammation occurs at a local region in a living body. Differentiation and maturation of lymphocytes, and the like are carried out at a specific site. More particularly, required various cells migrate and accumulate in the specific site and a sequence of inflammatory and immune responses arise. Thus, in addition to differentiation, proliferation and death of cells, cell migration is also an essential phenomenon to an immune system.
In the living body, migration of blood cells start with sifting hemopoiesis that started at AGM (Aorta Gonad Mesonephros) region via fetal liver to permanent hematopoiesis at bone marrow in a development course. Moreover, precursors of T cells and thymus dendritic cells migrate from fetal liver into bone marrow and then into the thymus gland. They differentiate under thymus environment. The T cells are subjected to clonal selection migrates into secondary lymphoid tissues, where they contribute to immune responses in periphery. Skin Langerhans cells that caught antigen, thereby undergone activation and differentiation migrate to T cell region in a topical lymph node, where they activate naive T cells therein as dendritic cells. The memory T cells again perform its homing into the lymph node via lymphatic and blood vessels. In addition, B cells, T cells in intestinal epithelia, γδT cells, NKT cells, and dendritic cells migrate from bone marrow not via thymus, differentiate and contribute to immune responses.
Chemokine is closely associated with such a migration of the various cells. For example, SDF-1 (Stromal cell derived factor-1) and its receptor, CXCR4 also act on various immune- and inflammatory reactions. For example, they have been reported to be associated with accumulation and activation of CD4+T cells in a synovial membrane from a human patient suffering from rheumatoid arthritis (J. Immunol., 165, 6590-6598 (2000)). In addition, in a CIA model mouse, CXCR4 inhibitor inhibited accumulation of leucocytes in a joint and dramatically reduced arthritis score (J. Immunol., 167, 4648-4692 (2001)). In a mouse OVA-induced airway hypersensitive model, an anti-CXCR4 antibody reduced the number of eosinophiles accumulating in pulmonary interstitial tissues and prevented airway hypersensitivity (J. Immunol., 165, 499-508 (2000)). In a mouse bleomycin-induced pulmonary disorder models, an anti-SDF-1 antibody inhibited invasion of fibrous cells to the lung and inhibited fibrosis of the lung (J. Clin. Invest., 114, 438-446 (2004)). In a mouse LPS-induced pneumonia model, it was observed that the number of neutrophils was increased with an increase in an SDF-1 concentration in an alveolar lavage fluid, and the number of neutrophils in the alveolar lavage fluid was prevented from being increased by administration of anti-SDF-1 antibody (J. Immunol., 178, 8148 (2007)). In a mouse retinopathy model, an anti-SDF-1 antibody inhibited vascular endothelial progenitor cell invasion to the retina and inhibited neovascularization at the retina (J. Clin. Invest., 115, 86-93 (2005)).
There has been reported that SDF-1 and its receptor, CXCR4 play an important role in maintaining hemopoietic stem cells in bone marrow (J. Exp. Med., 185, 111-120 (1997), Blood, 97, 3354-3360 (2001)). Accordingly, control of SDF-1 and CXCR4 is expected to modulate recruitment of hemopoietic stem cells to peripheral blood and are useful for peripheral blood stem cell transplantation and reproduction transplantation treatment.
SDF-1 and CXCR4 are associated with proliferation and infiltration of various cancer cells such as breast cancer, prostate cancer, ovarian cancer, medulloblastoma and the like (Nature, 410, 50 (2001), Cancer Res., 62, 1832 (2002), Cancer Res., 62, 5930 (2002), Proc. Nat. Acad. Sci. USA, 100, 13513 (2003)). In a model of transplanting a human breast cancer cell strain into a SCID mouse, an anti-CXCR4 antibody inhibited metastasis of breast cancer cells to lung (Nature, 410, 50-56 (2001)) and an anti-SDF-1 antibody inhibited neovascularization around cancer and inhibited proliferation of cancer cells (Cell, 121, 335 (2005)). In human ovarian epithelial tumor, highly expression of SDF-1 promotes accumulation of precursor cells of plasmacytoid dendritic cells which inhibit the act of T cells and suppresses tumor immune (Nat. Med., 12, 1339 (2001)). Moreover, SDF-1 is associated with proliferation and migration of non-Hodgkin's lymphoma cells, and in a model of transplanting a human non-Hodgkin's lymphoma cells into a NOD/SCID mouse, an anti-CXCR4 antibody inhibited proliferation of the tumor cells and improved mouse mortality (Cancer Res., 62, 3106-3112 (2002)). A low molecular weight CXCR4 antagonist increased apoptosis of medulloblastoma transplanted in the mouse skull and inhibited tumor proliferation (Proc. Nat. Acad. Sci. USA, 100, 13513 (2003)). In a lung metastasis model using malignant melanoma, the low molecular weight CXCR4 antagonist enhanced the antitumor effect of an immunostimulant and an anticancer drug (Mol Cancer Ther., 5, 2592 (2006)).
SDF-1 and CXCR4 play an important role for formation of hippocampus dentate gyrus granulocyte, that is essential for memory and learning and are associated with development of a disease associated with adult plasticity and pathology of hippocampus, for example Alzheimer's disease, stroke and epilepsy (Development, 129, 4249 (2002), Trends in Neurosci., 25, 548 (2002)).
SDF-1 and CXCR4 are essential for a function of self-reactive B cells associated with development of diabetes. In NOD mouse, an anti-SDF-1 antibody reduced blood glucose level and the number of mature IgM+B cells in a periphery tissue (Immunology, 107, 222 (2002)). In a human arteriosclerotic plaque, SDF-1 was highly expressed and activated blood platelets (Circ. Res., 86, 131 (2000)).
SDF-1 and CXCR4 are associated with residence of hemopoietic stem cells and hemopoietic precursor cells in bone marrow, and use of AMD3100 being CXCR4 antagonist in combination with G-CSF enabled an increase in the number of hemopoietic stem cells and hemopoietic precursor cells in peripheral blood (J. Exp. Med., 2001, 1307 (2005)). It is known that the number of neutrophils, lymphocytes and monocytes in peripheral blood are increased by administering a low molecular weight CXCR4 antagonist to human (Blood, 102, 2728-2730 (2003)). Therefore, the immunological enhancing effect is expected to the low molecular weight CXCR4 antagonist.
In addition, the results of SDF-1/CXCR4 knock-out mice showed that SDF-1 is essential for functions of central nervous tissue, heart and vessels of gastrointestinal tract in addition to lymphocytes (Nature, 382, 635 (1996), Nature, 393, 591 (1998), Nature, 393, 595 (1998)). Accordingly, it may be associated with a disease of these tissues.
Thus, chemokine receptors are expressed at various specific cells and at a specific time. They are largely associated with the control of inflammatory- and immune-responses through a mechanism by which their effector cells accumulate in a site where chemokine is produced.
Acquired immunodeficiency syndrome (also called AIDS) that caused by infection of human immunodeficiency virus (hereinafter abbreviated to HIV) is one of diseases for which therapies are the most eagerly desired lately. Once HIV infection has been established in a main target cell, CD4+cell, HIV repetitively proliferates in a patient's body and in the event deathly destroys T cells responsible for immunological functions. In this process, immunological functions are gradually deteriorated, various immunocompromised states become to develop such as fever, diarrhea and swelling of a lymph node, and various opportunistic infections such as carinii pneumonia are easily complicated. It is well known that such a state is the onset of AIDS and induces malignant tumors such as Kaposi's sarcoma and becomes severe.
Currently, there are tried various preventive and/or therapeutic treatments for AIDS as follows: for example, (1) inhibition of HIV proliferation by administration of reverse transcriptase inhibitors and protease inhibitors, and (2) prevention or alleviation of opportunistic infections by administration of an immunostimulant, etc.
HIV mainly infects helper T cells which play a key role in the immune system. Since 1985, it has been known that in this process HIV utilizes a membrane protein CD4 that is expressed on the membrane of T cells (Cell, 52, 631 (1985)). CD4 molecule consists of 433 amino acid residues and is expressed in macrophages, some B cells, vascular endothelial cells, Langerhans cells in skin tissues, dendritic cells located in lymphatic tissues, glia cells of central nervous system and the like in addition to mature helper T cells. However, as it becomes obvious that HIV infection cannot be established with only CD4 molecule, the possible presence of some factor that is responsible for infection of cell with HIV, other than CD4 molecule, has been suggested.
In 1996, a cell membrane protein called Fusin has been identified as a factor responsible for HIV infection other than a CD4 molecule (Science, 272, 872 (1996)). This Fusin molecule has been demonstrated to be a receptor for SDF-1, namely, CXCR4. In addition, it has been shown that SDF-1 specifically inhibits infection of T cell-directed (X4) HIV in vitro (Nature, 382, 829 (1996), Nature, 382, 833 (1996)). This may be considered that SDF-1 binds to CXCR4 prior to HIV, thereby taking away a scaffold for infecting a cell from HIV resulting in inhibition of HIV infection.
Also, at the same period, there has been found that another chemokine receptor CCR5, that is a receptor for RANTES, MIP-1α, and MIP-1β, is utilized at infection of macrophage-directed (R5) HIV (Science, 272, 1955 (1996)).
Namely, CXCR4 and CCR5 are expressed on a surface of host cells and both of them are employed as a coreceptor upon HIV infection.
Accordingly, those which can compete with HIV for CXCR4 and CCR5 or those which bind to a HIV virus and prevent for said virus from binding to CXCR4 and CCR5 may be a HIV infection inhibitor. In addition, there is a case where a low molecular weight compound discovered as a HIV infection inhibitor was showed to be indeed an antagonist of CXCR4 (Nat. Med., 4, 72 (1998)).
As described above, compounds having an antagonistic activity against CXCR4 are effective, such as, for prevention and/or the treatment of inflammatory and immune diseases, allergic diseases, infections (HIV infection, etc.), diseases associated with HIV infection (acquired immunodeficiency syndrome, etc.), cancer, cancer metastasis, psychoneurotic diseases, cardiovascular diseases, metabolic diseases and cancerous diseases, and are also useful for regeneration therapy.
Heretofore, the following compound has been reported. For example, it is disclosed that a compound represented by formula (R):
(wherein n1r, n2r and n3r represent 0 to 3; R1R, R2R, R3R, R4R, R5R, R6R each independently represents a hydrogen atom or an optionally substituted C1-15 alkyl group, etc.; A1R and A2R each independently represents an optionally substituted monocyclic or polycyclic heterocyclic aromatic ring, etc.; WR represents an optionally substituted C1-15 alkylene group, etc.; XR represents 0, CH2 or NR11R, etc.; R11R represents a hydrogen atom or an optionally substituted C1-15 alkyl group, etc.; DR represents -QR-YR—BR, in which QR represents a bond or —CO— when XR is NR11R, YR represents —(CR18RR19R)m3r—, R18R and R19R each independently represents a hydrogen atom or an optionally substituted C1-15 alkyl group, etc.; m3r represents 0 to 6; BR represents —NR25RR26R, etc.; and R25R and R26R represent a hydrogen atom or an optionally substituted C1-15 alkyl group when XR is not CH2, etc.; and only required portions were extracted with respect to definition of each group), or a pharmaceutically acceptable salt thereof, or a prodrug thereof has an antagonistic activity against CXCR4. However, compounds having a spiro-bound cyclic group are not disclosed (refer to Patent Document 1).
It is disclosed that a compound represented by formula (S):
(wherein WS represents a C6-12 aralkyl optionally having a substituent, etc.; XS, YS and ZS each independently represents —CO— or —CH2—, etc.; R1S represents a hydrogen atom, a hydroxyl group or a C1-10 alkyl which may have a substituent(s), etc.; R2S represents an alkyl which may have a substituent(s), etc.; R3S represents a hydrogen atom or an alkyl group which may have a substituent(s), etc.; and only required portions were extracted with respect to definition of each group), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof has an antagonistic activity against CCR5. However, it is not disclosed to have an antagonistic activity against CXCR4 (refer to Patent Document 2).
It is disclosed that a compound represented by formula (T):
(wherein A1T and A2T each independently represents a nitrogen-containing heterocyclic group which may have a substituent(s), etc.; B1T, B2T and GT u each independently represents —CO—, —SO2—, or —CH2—, etc.; DT represents a carbon atom or a nitrogen atom; ET represents a cyclic group, etc.; LT represent a bond or a spacer having 1 to 4 atom(s) in its main chain; JT represents (1) a cyclic group which is substituted with a group having a basic group, and also may have a substituent(s)) or (2) a spirocyclic group which can be substituted with a group having a basic group, and also may have a substituent(s), provided that any one of B1T, B2T and GT u represents —CO— or —SO2—; and only required portions were extracted with respect to definition of each group), a salt thereof, an N-oxide thereof or a solvate thereof, a prodrug thereof has an antagonistic activity against CXCR4 (refer to Patent Document 3).
It is disclosed that a compound represented by formula (U):
(wherein A1U and A2U each independently represents a nitrogen-containing heterocycle which may have a substituent(s), etc.; B1U and B2U each independently represents a bond or —CH2—, etc.; EU represents a 3- to 8-membered monocyclic cyclic group which may have a substituent(s), etc.; LU represents a bond, —CH2— or —CH2—NH—, etc.; Ju represents (1) a monocyclic or condensed cyclic group which is substituted with a group having a basic group, and also may have a substituent(s), or (2) a spiro-bound cyclic group which may be substituted with a group having a basic group, and also may have a substituent(s), etc.; GU represents —CO—, —CH2—, —CH(OH)— or —NH—, etc.; RU represents a hydrogen atom or a substituent; and only required portions were extracted with respect to definition of each group), a salt thereof, an N-oxide thereof or a solvate thereof or a prodrug thereof has an antagonistic activity against CXCR4 (refer to Patent Document 4).
It is disclosed that a compound represented by formula (V):
(wherein A1V and A2V each independently represents a nitrogen-containing heterocyclic group which may have a substituent(s), etc.; B1V and B2V each independently represents —CO—, —SO2— or —CH2—, etc.; GV represents a bond, —CO—, —SO2— or —CH2—, etc.; EV represents cyclic group which may have a substituent(s), etc.; LV represents a bond or spacer having 1 to 4 atom(s) in its main chain; JV represents (1) a cyclic group which is substituted with a group having a basic group, and may also have a substituent(s), or (2) spirocyclic group which may be substituted with a group having a basic group, and also may have a substituent(s), etc.; and only required portions were extracted with respect to definition of each group), a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof has an antagonistic activity against CXCR4 (refer to Patent Document 5).
(wherein M1W and M2W each independently represents a group having an acidic group which may be protected with a protective group; A1W and A2W each independently represents a nitrogen-containing heterocycle which may have a substituent(s); B1W and B2W each independently represents a bond, —CO—, —SO2— or —CH2—, etc.; GW represents a bond, —CO—, —SO2— or —CH2—, etc.; EW represents a cyclic group which may have a substituent(s), etc.; LW represents a bond or spacer having 1 to 4 atom(s) in its main chain; JW represents (1) a cyclic group which is substituted with a group having a basic group, and also may have a substituent(s), or (2) spirocyclic group which may be substituted with a group having a basic group, and also may have a substituent(s), etc.; and only required portions were extracted with respect to definition of each group), a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof has an antagonistic activity against CXCR4 (refer to Patent Document 6).
It is disclosed that a compound represented by formula (X):
(wherein A1X represents a nitrogen-containing heterocycle which may have a substituent(s), etc.; ring A2X represents a divalent monocyclic cyclic group which may have a substituent(s); E1X represents a divalent C1-4 aliphatic hydrocarbon group which may have a substituent(s); E2X represents a methylene group or a carbonyl group; R3X represents (1) a hydrogen atom, (2) a hydroxyl group which may be protected with a protective group, a carboxyl group which may be protected with a protective group, or a C1-4 aliphatic hydrocarbon group which may be substituted with a sulfo group which may be protected with a protective group, and also may have a substituent(s), etc.; GX represents:—(CH3)p—(in the group, p represents an integer of 1 to 4), etc.; ring J1X represents a 3- to 10-membered monocyclic or dicyclic heterocycle which has at least one nitrogen atom, and also may have an oxygen atom or an optionally oxidized sulfur atom; ring J2X represents (i) a C3-10 monocyclic or dicyclic carbon ring which is substituted with a group having a basic group, (ii) a 3- to 10-membered monocyclic or dicyclic heterocycle composed of a carbon atom, an oxygen atom and/or an optionally oxidized sulfur atom, which is substituted with a group having a basic group, or (iii) a 3- to 10-membered monocyclic or dicyclic heterocycle which may be substituted with a group having a basic group, and also has at least one nitrogen atom and may have an oxygen atom and/or an optionally oxidized sulfur atom; and ring J1X and ring J2X may have 1 to 8 substituents on the substitutable position and, when 2 or more substituent are present, a plurality of the substituents may be the same or different), a salt thereof, an N-oxide thereof, or a solvate thereof, or a prodrug thereof has an antagonistic activity against CXCR4 (refer to Patent Document 7).
It is disclosed that a compound represented by formula (Y):
(wherein n1y, n2y and n3y represent 0 to 3; R1Y, R2Y, R3Y, R4Y, R5Y and R6Y each independently represents a hydrogen atom or an optionally substituted C1-15 alkyl group, etc.; A1Y and A2Y each independently represents a hydrogen atom or an optionally substituted monocyclic or polycyclic heterocyclic aromatic ring, etc.; WY represents an optionally substituted benzene ring, etc.; XY represents an optionally substituted monocyclic or polycyclic heterocyclic aromatic ring, an optionally substituted monocyclic or polycyclic aromatic ring, O, CH2, NR11Y or CHR35Y, etc.; R11Y represents a hydrogen atom or an optionally substituted C1-15 alkyl group, etc.; CHR35Y represents a carboxyl group, an alkoxycarbonyl group or a carbonyl group; DY represents -QY-YY—BY, in which QY represents a bond or —CO— when XY is NR11Y, etc.; YY represents —(CR18YR19Y)m3y—, etc.; R18Y and R19Y each independently represents a hydrogen atom or an optionally substituted C1-15 alkyl group, etc.; m3y represents 0 to 6; BY represents —NR25YR26Y, etc.; and R25Y and R26Y represent a hydrogen atom or an optionally substituted C1-15 alkyl group when XY is not CH2, etc.; and only required portions were extracted with respect to definition of each group), or a pharmaceutically acceptable salt thereof, or a prodrug thereof has an antagonistic activity against CXCR4. However, compounds having a spiro-bound cyclic group are not disclosed (refer to Patent Document 8).
However, Patent Documents 3 and 5 do not disclose specific compound having a carboxyl group. Patent Document 4 discloses a compound having a carboxyl group. However, activity of the compound was too insufficient to be formed into pharmaceuticals. Patent Documents 6 and 7 disclose that toxicity is avoided in a compound having a carboxyl group. However, there was neither description nor suggestion about stability in blood (elimination rate in blood) of these compounds and, actually, stability in blood of these compounds was insufficient.